During the depressed phase of major depressive disorder and bipolar disorder, glucose metabolism is abnormally elevated in the amygdala, a brain structure that is critically involved in associating experiential stimuli with emotional significance and in organizing the endocrine, autonomic and behavioral responses to emotional stimuli. The magnitude of this elevation correlated positively with blood concentrations of the stress hormone cortisol. This relationship may reflect two phenomena that have been established in studies of rodents: the amygdala?s prominent role in mediating corticosterone (the rodent equivalent of cortisol) secretion during stressful conditions, and the direct enhancement of amygdala function by corticosterone. In response to viewing pictures of human faces showing sad expressions, the neural responses of the amygdala and the prefrontal cortex were abnormal in the depressed phase of both bipolar disorder and major depressive disorder. In both depressed and healthy control subjects the blood flow initially increased in the amygdala in response to sad faces. However, after repeatedly viewing the same sad faces, the amygdala stopped responding in the healthy subjects, but continued to respond in the depressed subjects. This abnormality was associated with abnormal responses of the prefrontal cortex to sad faces in the depressives, such that activity in the anterior cingulate and orbital cortex increased in healthy subjects, but decreased in depressed subjects. These latter regions play important roles in regulating emotional responses generally, including those mediated by the amygdala. During the past one year three functional imaging experiments have been conducted to pursue these findings, and a fourth has now been initiated as well. One involved an investigation of the neural basis for the catastrophic response to perceived failure which depressed patients show. This study uses fMRI imaging during a probabilistic reversal learning task to elicit and characterize these phenomena. This study demonstrated initially a significant behavioral difference between depressives and controls, and a manuscript is in preparation to describe these results. During the past year, the image acquisition for this protocol was completed, the results were analyzed, and a manuscript describing these data is in preparation. The second imaging experiment investigated the effects of antidepressant drugs on amygdala responses to emotionally valenced faces. The pilot study initially characterized the optimal stimulus parameters needed to elicit the amygdala responses. These results are of broad interest to the human brain mapping community and will be presented at the Annual Meeting of the Society for Neuroscience. The study of the depressed subjects was initiated and now a total of 20 depressed subjects and 20 healthy controls have been imaged. Many of the depressed subjects have been reimaged following fluoxetine treatment. The third study examined the rates at which depressives and controls are able to habituate to amygdala responses during repeated stimulation. Nineteen healthy volunteers were studied during the task development for this protocol. The data are being analyzed. During the coming year depressed subjects will be entered to investigate abnormalities of neural regulation during emotional processing in depression. Two manuscripts are in preparation describing these results. The new and fourth functional neuroimaging study that was conducted involved examination of the effects of catecholamine depletion, induced using the catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine (AMPT), on cerebral glucose metabolism and on the neural responses to emotionally valenced stimuli in both recovered cases with MDD and in healthy controls. The data acquisition was completed for this protocol during this past year. Thirteen clinically remitted patients with a history of MDD and 13 healthy controls were scanned under both the placebo and AMPT conditions. The behavioral results confirmed previous evidence that this manipulation increases depressive symptoms in the recovered MDD cases. In addition, they demonstrated and characterized for the first time a greater vulnerability of the recovered MDD cases to develop anhedonia (inability to experience pleasure) and anxiety during the depletion, and hypomanic symptoms the day following the study in the recovery phase. Two manuscripts describing these results have been submitted for publication. Finally, the previously conducted PET study assessing the effects of pramipexole on cerebral glucose metabolism was completed and the results analyzed. A manuscript is in press in Biological Psychiatry to report that these data showed that the functional anatomical abnormalities present in unmedicated subjects with MDD also are evident in lithium treated bipolar subjects who are currently depressed. In addition, a manuscript reporting that pramipexole treatment resulted in prominent reductions of metabolic activity in these regions is nearly complete.